Crystalline monohydrate clopidogrel naphthalenedisulfonate and process of preparation

Abstract

A crystalline clopidogrel naphthalenesulfonate or a hydrate thereof, a method for preparing same, and a pharmaceutical composition containing same are provided.

1. A crystalline monohydrate of clopidogrel 1,5-naphthalenedisulfonate represented by formula (Ib) 
       
         
           
           
               
               
           
         
       
     
     
       2. The crystalline monohydrate of clopidogrel 1,5-naphthalenedisulfonate of  claim 1 , whose powder X-ray diffraction scan shows major peaks having I/I 0 values greater than 10% at 2θ=7.6, 9.7, 10.7, 11.0, 12.1, 13.6, 14.2, 15.3, 16.6, 17.0, 18.1, 18.5, 19.8, 21.5, 22.2, 23.0, 23.5, 24.3, 24.8, 25.7, 26.4, 26.9, 27.3, 28.4, 29.0. 
     
     
       3. A method for preparing a crystalline monohydrate of clopidogrel 1,5 -naphthalenedisulfonate of formula (Ib), which comprises: 
       
         
           
           
               
               
           
         
       
       reacting a clopidogrel free base of formula (II) 
       
         
           
           
               
               
           
         
       
       with a 1,5-naphthalenedisulfonic acid hydrate, in an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, methanol, tetrahydrofuran, 1,4-dioxane and a mixture thereof. 
     
     
       4. The method of  claim 3 , wherein the crystalline monohydrate of clopidogrel 1,5-naphthalenedisulfonate is characterized in the powder X- ray diffraction scan by showing major peaks having I/I 0  values greater than 10% at 2θ=7.6, 9.7, 10.7, 11.0, 12.1, 13.6, 14.2, 15.3, 16.6, 17.0, 18.1, 18.5, 19.8, 21.5, 22.2, 23.0, 23.5, 24.3, 24.8, 25.7, 26.4, 26.9, 27.3, 28.4, 29.0. 
     
     
       5. The method of  claim 3 , wherein the 1,5-naphthalenedisulfonic acid hydrate is employed in an amount ranging from 0.5 to 0.6 moles based on 1.0 mole of the clopidogrel free base. 
     
     
       6. A pharmaceutical composition comprising the crystalline monohydrate of clopidogrel 1,5 -naphthalenedisulfonate of  claim 1  as an active ingredient in the presence of a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
       7. The pharmaceutical composition of  claim 6 , wherein the crystalline monohydrate of clopidogrel 1,5-naphthalenedisulfonate is present in the amount ranging from 0.1 to 95% by weight based on the total weight of the composition in oral dosage unit. 
     
     
       8. The pharmaceutical composition of  claim 6 , wherein the crystalline monohydrate of clopidogrel 1,5-naphthalenedisulfonate is present in the amount ranging from 1 to 70% by weight based on the total weight of the composition in oral dosage unit. 
     
     
       9. The pharmaceutical composition of  claim 6 , wherein the crystalline monohydrate of clopidogrel 1,5-naphthalenedisulfonate is characterized in the powder X-ray diffraction scan by showing major peaks having I/I 0 values greater than 10% at 2θ=7.6, 9.7, 10.7, 11.0, 12.1, 13.6, 14.2, 15.3, 16.6, 17.0, 18.1, 18.5, 19.8, 21.5, 22.2, 23.0, 23.5, 24.3, 24.8, 25.7, 26.4, 26.9, 27.3, 28.4, 29.0. 
     
     
       10. The method of  claim 3 , wherein the organic solvent contains water up to 15% by volume based on the total volume of the organic solvent.